Production of humoral antibody to red cell-bound antigen proceeds through a coordinated sequence of differentiation and proliferation steps by antigen-reactive precursor B cells. The response depends on helper cells, macrophages and T cells, which control distinct phases of B cell activation through soluble mediators (lymphokines). The concept investigated here distinguishes three phases of B-cell activation: (1)\an early phase of B-cell differentiation, controlled by the macrophage product interleukin-1, in which antigenreactive B cell precursor becomes responsive to T cell-dependent helper factors; (2)\a subsequent proliferation phase (clonal expansion) which is controlled by the T cell product interleukin-2 and; (3)\a terminal differentiation phase in which nonsecreting B cells convert into antibodysecreting cells. The latter phase is controlled by a mediator referred to here as TRF, presumably released by T cells. In the past, our studies have been concerned with the production of antibody to cellular antigen. We plan now to test the validity of the concepts obtained for the mechanism of antibody production to soluble antigen. We will focus our interest on a T-cell subset which acts to convert resting precursor B cells into cycling, lymphokine-responding cells. This "initiator" T cell appears to be required for antibody formation to soluble antigen but not for antibody formation to cellular antigen. While most of our experiments are concerned with the generation of IgM antibody-producing cells, we also will try to obtain a better understanding of mechanisms leading to the production of IgG antibody-forming B cells. Our interest here lies in the relationship of the IgG response to the IgM response and in the role of helper factors. The work will be conducted with laboratory mice.